Syphilis is a chronic, sexually transmitted disease of humans caused by the spirochetal bacterium Treponema pallidum. The disease's recent dramatic resurgence, coupled with the recognition that syphilitic genital ulcers facilitate transmission of the human immunodeficiency virus (HIV), underscore the importance of studies to elucidate its complex pathogenesis. The inability to cultivate T. pallidum in vitro and the consequent lack of a genetic exchange system continue to hamper efforts to identify virulence factors potentially influencing the pathogenesis of the disease. This lack of information historically has undermined the rational design of immunological intervention strategies for syphilis. Based upon a number of discoveries made by the PI, we shall continue to focus on elucidating the structure-function relationships of T. pallidum membrane lipoproteins as a means of clarifying the role of T. pallidum membrane biology in host-parasite interactions and immunopathogenesis processes. Accordingly, the Specific Aims of this proposal are: (1) To investigate the biological relevance of our discovery that the 47-kDa major membrane lipoprotein of T. pallidum is a penicillin-binding protein with carboxypeptidase activity; (2) To assess whether the 38-kDa lipoprotein, a homolog of the E. coli glucose/galactose-binding (MglB) protein, is a glucose receptor potentially involved in sensory transduction, and to characterize the newly discovered mgl operon of T. pallidum within the context of syphilis pathogenesis; (3) To examine in vivo and in vitro immune cell activation events promoted by synthetic analogs of T. pallidum lipoproteins; and (4) To investigate whether cell activation by T. pallidum lipoprotein-analogs enhance HIV replication in chronically infected macrophages. The pursuit of these Aims will simultaneously advance our understanding of features of T. pallidum membrane biology relevant to syphilis pathogenesis as well as the molecular constituents which induce salient inflammatory processes that culminate in clinical disease.